tbuckley/cabot-search huggingface dataset:
Abstract 155: An endosomal type Igamma PIP 5-kinase controls endosome maturation, lysosome function, and autophagy by modulating Rab7a
Authors: Ming Sun, Gary Luong, Faiz Plastikwala, Yue Sun
Journal: Cancer Research (2022)

Abstract Endosomes are major protein-sorting stations in cells. Defects in endosomal sorting are implicated in various human pathologies, such as cancer and neurodegenerative disorders. The small GTPase Ras-related protein Rab-7a (Rab7a) serves as a key organizer of the endosomal-lysosomal system. However, molecular mechanisms controlling Rab7a activation levels and subcellular translocation are still poorly defined. Here, we demonstrate that type Igamma phosphatidylinositol phosphate 5-kinase i5 (PIPKIgammai5), an endosome-localized enzyme that produces phosphatidylinositol 4,5-bisphosphate (PI4,5P2), directly interacts with Rab7a and plays critical roles in the control of endosomal-lysosomal system. The loss of PIPKIgammai5 blocks Rab7a recruitment to early endosomes, which prevents the maturation of early to late endosomes. In this way, PIPKIgammai5 is required for Epidermal Growth Factor Receptor (EGFR) sorting from endosomes to lysosomes, which controls the down-regulation of EGFR signaling. Furthermore, PIPKIgammai5 loss disturbs retromer complex connection with Rab7a, which blocks the retrograde sorting of Cation-independent Mannose 6-Phosphate Receptor (CI-MPR) from late endosomes. This leads to the decreased sorting of hydrolases to lysosomes. Thus, loss of PIPKIgammai5 causes lysosome dysfunction and reduces the autophagic degradation. By modulating retromer-Rab7a connection, PIPKIgammai5 is also required for the recruitment of the GTPase-activating protein (GAP) TBC1 domain family member 5 (TBC1D5) to late endosomes, which controls the conversion of Rab7a from the active state to the inactive state. Altogether, PIPKIgammai5 is critical for the modulation of Rab7a activity, localization, and function in the endosomal-lysosomal system. Citation Format: Ming Sun, Gary Luong, Faiz Plastikwala, Yue Sun. An endosomal type Igamma PIP 5-kinase controls endosome maturation, lysosome function, and autophagy by modulating Rab7a [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 155.
Abstract 2635: Inhibiting deoxycytidine kinase significantly inhibits tumor growth in xenograft models of castration resistant prostate cancer
Authors: Caius G. Radu, Kenneth A. Schultz, Katharina Lückerath, H Michael Shepard, Johannes Czernin
Journal: Cancer Research (2022)

Abstract Mammalian cells synthesis deoxyribonucleoside triphosphate (dNTP) precursors for DNA replication via the de novo pathway (DNP), and to a lesser extent, via the nucleoside salvage pathway (NSP). Evidence suggests that rapid tumor cell growth associated with increased dNTP needs results in elevated NSP activity. As deoxycytidine kinase (dCK) is the rate-limiting enzyme of the NSP, and the only enzyme that can supply cells with all dNTP precursors for DNA replication, dCK has been implicated as a promising therapeutic target. Data from the Cancer Cell Line Encyclopedia demonstrated that most human cancer cell lines have elevated dCK gene expression (2- to 17-fold) therefore suggesting selective susceptibility of tumor cells to dCK inhibition. Accordingly, a potent first-in-class oral dCK inhibitor, TRE-515, was evaluated as a single agent in two human castration-resistant prostate cancer (CRPC) models. In the first CRPC model, C4-2, TRE-515 was administered intraperitoneally once a day for eight consecutive days (50 mg/kg, QDx8). TRE-515 significantly inhibited tumor growth (50.7%, p=0.021, relative to vehicle control), with 50% of the TRE-15 treated tumors regressing during the eight-day treatment window. In a repeat C4-2 study, TRE-515 monotherapy trended toward tumor growth inhibition, (53.7%, p=0.061, relative to vehicle control). A second CRPC model, 22Rv1, was then selected as it has been shown to carry DNP mutations, suggesting enhanced sensitivity to dCK inhibition. In this study, TRE-515 was dosed orally two times a day for 28 days (75 mg/kg, BIDx28) and plasma deoxycytidine (dC) concentrations (a substrate for dCK) were measured 7 hours after the morning dose on day 21. TRE-515 alone significantly inhibited tumor growth (49.9%, p=0.0004, relative to vehicle control), and growth inhibition was associated with a 77% increase in plasma dC levels (p&amp;lt;0.0001), relative to vehicle control, consistent with TRE-515 inhibitory activities on dCK. These data are in agreement with a previously reported study on target enzyme inhibition by TRE-515 which employed a clinically validated PET probe imaging of dCK. Taking together these results support the therapeutic potential for TRE-515 to selectively inhibit cancer cells that rely on dCK for DNA synthesis and rapid malignant proliferation. As such, TRE-515 is currently being evaluated in a phase 1 open-label, dose escalation study in solid tumors (NCT #05055609). Citation Format: Caius G. Radu, Kenneth A. Schultz, Katharina Lückerath, H Michael Shepard, Johannes Czernin. Inhibiting deoxycytidine kinase significantly inhibits tumor growth in xenograft models of castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2635.
Abstract 3465: Efficacy of concomitant application of Tumor Treating Fields (TTFields), temozolomide and lomustine in glioblastoma cancer cells <i>in vitro</i>
Authors: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2022)

Abstract Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Newly diagnosed GBM (ndGBM) is treated with adjuvant temozolomide (TMZ), however, more than 50% of patients do not respond to therapy. Tumor Treating Fields (TTFields) therapy concomitant with maintenance TMZ was approved by the FDA in 2015 and represents a major advance in treatment of patients with ndGBM. Recently, lomustine (CCNU) together with TMZ demonstrated improved overall and progression-free survival following resection and radiochemotherapy in patients with ndGBM. Accordingly, the current study aimed to examine the effect of concomitant application of TTFields with TMZ and CCNU in GBM cells. Methods: GBM cells (U-87 MG and LN229) were treated for 72 h with TTFields at a frequency of 200 kHz and an intensity of 1 V/cm RMS using the inovitro system. Efficacy of combining TTFields with TMZ and/or CCNU was tested by measuring cell survival, clonogenic potential, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction. Results: Combination of TMZ and TTFields resulted in increased cytotoxicity compared with each treatment alone. The cytotoxic effect resulting from co-application of CCNU with TTFields suggested a synergistic interaction between the two modalities. The clonogenic, overall, and apoptotic effects of TMZ and CCNU were also enhanced following co-treatment with TTFields. The triple combination of TTFields with both TMZ and CCNU was more efficacious than TMZ/CCNU or TTFields separately. Conclusions: The current research suggests potential benefits for the treatment of GBM using concomitant application of TTFields with TMZ/CCNU. Citation Format: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Efficacy of concomitant application of Tumor Treating Fields (TTFields), temozolomide and lomustine in glioblastoma cancer cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3465.
Abstract 816: Cyclin c suppresses pancreatic intraepithelial neoplasm progression and neuroendocrine neoplasm development in a murine Kras model
Authors: Kathy Q. Cai, Sara E. Hanley, Andres Klein-Szanto, Kerry S. Campbell, Randy Strich
Journal: Cancer Research (2022)

Abstract Cyclin c is a component of the Cdk8 kinase module that plays both a positive and negative role in transcription. In addition, cellular damage induces cyclin c re-localization to the mitochondria where it stimulates fission and recruits Bax in preparation for apoptotic initiation. Previous studies revealed that cyclin c suppresses thyroid hyperplasia in a Pten knockout mouse model. In the present study, a role for cyclin c in suppressing pancreatic cancer progression was investigated in the Pdx1-Cre LSL-KrasG12D murine pancreatic cancer model. Within eight weeks, a 6-8 fold increase in the appearance of pancreatic intraepithelial neoplasia (PanIN) and acinar ductal metaplasia (ADM) lesions was observed in the KrasG12D+Ccnc-/- animals compared to KrasG12D alone. Surprisingly, high-grade neuroendocrine neoplasms (NEN) were also observed. These aggressive NEN showed mixed morphology with areas of acinar-like differentiation. High grade NEN exhibited pronounced proliferative index (Ki67), high EZH2 expression, and elevated Notch1, suggesting a connection between aberrant Notch signaling and NEN formation. Our previous studies identified a positive role for cyclin c in autophagy gene transcription. Similarly, cell lines derived from a KrasG12D+Ccnc-/- pancreas exhibited a reduction in autophagy compared to KrasG12D+Ccnc+/+ cells. Autophagic deficiency induces pancreatic cell stress and is associated with apoptosis. Consistent with this model, high caspase 3 expression was observed in early KrasG12D+Ccnc-/- NEN but not in KrasG12D+Ccnc+/+ tissues. Taken together, these results demonstrate a role for cyclin c in suppressing both progression of early PanIN and the development of high-grade NEN and suggest a model that cyclin c loss suppresses autophagy and increases apoptosis. Acknowledgements: Support was provided by NCI CCSG grant CA06927 for the FCCC Histopathology and Cell Culture Facilities, the PA Department of Health CURE fund (KSC), the Boye Foundation (RS), and the New Jersey Health Foundation (RS). Citation Format: Kathy Q. Cai, Sara E. Hanley, Andres Klein-Szanto, Kerry S. Campbell, Randy Strich. Cyclin c suppresses pancreatic intraepithelial neoplasm progression and neuroendocrine neoplasm development in a murine Kras model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 816.
Abstract 1812: Therapeutic targeting and development of IDH inhibitors for the treatment of chondrosarcoma
Authors: Tahir N. Sheikh, Chao Lu, Gary K. Schwartz
Journal: Cancer Research (2022)

Abstract Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Recurrent somatic mutations in the isocitrate dehydrogenase I (IDH1) genes have been identified in a spectrum of human malignancies, including chondrosarcoma. Mutations in these genes lead to impaired ability of IDH1 to catalyze the conversion of isocitrate to alpha ketoglutarate and to gain of a neomorphic enzymatic activity which results in production of oncometabolite 2-hydroxyglutarate (2HG). Our preliminary data indicated that compared to samples that were wild type, IDH1 mutant samples showed a significant increase in intra-tumoral 2HG levels. In the present study, we hypothesized that 2-HG accumulation induces DNA and histone hypermethylation and altered gene expression, ultimately resulting in a block in cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Therefore, we proposed that inhibition of IDH should mediate its antitumor effects through the induction of differentiation. To test this hypothesis, we utilized human chondrosarcoma cell lines including IDH wild type (CH2879) and IDH1 mutant (JJ012) and the IDH1 inhibitor FT6535. Results from our in vitro cell viability assay and histone methylation showed that selective inhibition of IDH1 resulted in modest inhibition of cell proliferation and suppression of histone methylation in IDH1 mutant chondrosarcoma cells. Next we elected to test the IDH inhibitor in combination with differentiating agents including retinoic acid. Cell viability assays showed that when compared to either agent alone, the combination of retinoic acid and FT6535 resulted in a significant decrease in cellular proliferation. Western blot analysis showed induction of COL1A2 and SOX9 (differentiation markers) with suppression of histone methylation H3K27me3 or H3K9me3, Taken together, our data strongly suggests that combination treatment with the IDH1 inhibitor FT6535 and retinoic acid represents a novel approach to suppress cell growth by epigenetic modulation to induce differentiation and merits further evaluation as a potential treatment modality in chondrosarcoma. Citation Format: Tahir N. Sheikh, Chao Lu, Gary K. Schwartz. Therapeutic targeting and development of IDH inhibitors for the treatment of chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1812.
Abstract 6295: Grape seed procyanidins inhibit cell proliferation &amp; induce apoptosis in both human breast &amp; liver cancer cell lines
Authors: Rana Hamed Alneanaey, Nabil Taha, Mohammed Lebda, Aml Hashem, Ahmed Sultan
Journal: Cancer Research (2022)

Abstract As a potential anticancer agent, grape seed procyanidins (GSPs) have been shown to be effective in treating and preventing various cancer types, but the mechanistic inhibitory effect at cellular and molecular levels in most of the cancer types remains unclear. The objective of the present study was to investigate the potential influence of GSPs on both liver and breast cancers. The anticancer efficacy of GSPs was investigated in vitro, using two human cancer cell lines; human hepatocellular carcinoma (HepG2) and human breast carcinoma, Zr-75-1.The potential influence of extracted GSPs was examined on cell proliferation, clonogenic assays, morphological alteration, and western blot was used to analyze the expression of oncogenic signaling pathways of STAT3, β-catenin, T-ERK, and pERK, Bax, Bcl-2, mutant-p53, and caspase enzyme activity assay was measured by caspase colorimetric assay.Our data showed that GSPs treatment inhibits both cellular viability and proliferation in a concentration-and time-dependent fashion in both breast and liver cancer cell lines after 48h. Furthermore, mechanistic studies showed that GSPs induced late apoptosis by 72% that was associated with cell morphological changes, histone release from fragmented DNA, caspase-3 activation in a dose-dependent manner after 48h. Furthermore, GSPs down-regulated pERK, STAT3, β-catenin, and mutant p53 levels as well as increased p21and Bax, pro-apoptotic signal, in both breast and liver cancer cells as determined by western blot analysis. All in all, our findings suggest that GSPs inhibit breast and liver cancer cells proliferation and induce cell apoptosis by suppressing the oncogenic signaling pathways that play a role in cancer progression which in turn introduce GSPs as a promising phytochemical for cancer treatment. Citation Format: Rana Hamed Alneanaey, Nabil Taha, Mohammed Lebda, Aml Hashem, Ahmed Sultan. Grape seed procyanidins inhibit cell proliferation &amp; induce apoptosis in both human breast &amp; liver cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6295.
Abstract 2691: Expression pattern and prognostic significance of HER family members and EGFRvIII in pancreatic cancer
Authors: Tanzeel Khan, Said A. Khelwatty, Izhar Bagwan, Alan Seddon, Angus Dalgleish, Satvinder Mudan, Helmout Modjtahedi
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is one of the most aggressive, heterogeneous, and fatal types of human cancers. There is urgent need for discovery of biomarkers of prognostic significance, predictive value and as well as therapeutic targets in patients with pancreatic cancer. In this study, we examined the relative expression and prognostic significance of all HER family members and the type III EGFR mutant (EGFRvIII) in patients with pancreatic ductal adenocarcinoma (PDC). The expression levels of wild-type EGFR (wtEGFR), HER2, HER3, HER4 and EGFRvIII were determined in tumor specimens from 43 patients by immunohistochemistry using antibodies DAK-H1-WT, Neu 3B5, SP71, HFR1 and NBP2-50599 respectively. The staining was scored based on the percentage of positive tumor cells, the intensity (i.e. strong 3+, moderate 2+, weak 1+) and the cellular location of immunostaining (i.e. membranous, cytoplasmic or nuclear). The association between the expression level of the biomarkers and patient overall survival was evaluated using Chi-squared, Kaplan-Meier survival curves and log rank test. At cut-off value of above 5%, we found weak to moderate expression of wtEGFR, HER2, HER3, HER4 and EGFRvIII in 4.7%, 14%, 14%, 20.9% and 2.3% of the cases examined respectively. The cellular location of wtEGFR and HER2 was found to be predominantly cytoplasmic, HER-3 membranous and cytoplasmic whereas HER4 expression was found to be mainly nuclear. There was no statistically significant association between the expression level of these markers and patient overall survival. The expression levels of the above biomarkers were also evaluated in tissue microarrays (TMAs) from 40 cases of pancreatic ductal adenocarcinoma. Interestingly, at the same cut-off value, 62.5%, 75%, 0%, 55% and 5% of the TMAs were positive for wtEGFR, HER2, HER3, HER4 and EGFRvIII respectively. Overall, we found that the expression pattern of HER family members was heterogenous, and with EGFRvIII expression being very low in both whole tumor sections and TMAs from patients with pancreatic cancer. Taken together, our results provide support for more detailed studies of co-expression of all HER family members in a larger group of pancreatic cancer patients. Such studies should help to unravel their potential as targets for therapeutic interventions as well as their prognostic significance and predictive value for response to therapy. Citation Format: Tanzeel Khan, Said A. Khelwatty, Izhar Bagwan, Alan Seddon, Angus Dalgleish, Satvinder Mudan, Helmout Modjtahedi. Expression pattern and prognostic significance of HER family members and EGFRvIII in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2691.
Abstract 6137: Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness
Authors: Danila Del Rio, Valentina Caprara, Ilenia Masi, Francesca Spadaro, Sara Giannitelli, Alberto Rainer, Anna Bagnato, Laura Rosanò
Journal: Cancer Research (2022)

Abstract The recruitment of fibroblasts to tumor and their activation to cancer-associated fibroblast (CAF) is an exploited strategy used by tumor to guide matrix remodeling, supporting cancer invasion and metastatic disease. CAFs are the major effectors of extracellular matrix (ECM) remodelling through secretion of collagens, cross-linking enzymes and proteases, and in turn engagement of integrins. Although several tumor cell-secreted factors have been identified in generating tumor-promoting stroma, there has been a great interest to define factors and associated molecular mechanisms involved in promoting CAF premetastatic function. Tumor-related endothelin-1 (ET-1) has an important role in the crosstalk between cancer and stromal cells supporting serous ovarian cancer (SOC) progression. By binding its receptors (ETAR and ETBR), ET-1 favours the recruitment of the protein β-arrestin-1 and the generation of signaling complexes regulating also cytoskeleton reorganization, thereby fine-tuning SOC cell invasion and metastasis. However, how the integration of ET-1 receptors might “educate” stroma to become permissive for invasion, supplying an altered ECM governing metastasis needs to be investigated. In this study, we identified endothelin-1 as a key factor in priming CAF conversion in SOC. We demonstrate that primary ovarian fibroblasts express ETA and ETB, along with β-arrestin1, and secrete ET-1; b) the autocrine and cancer-secreted ET-1 promotes fibroblast proliferation, and an increase in the expression of CAF markers (αSMA, vimentin and FAP), secretion of proinflammatory cytokines, collagen contraction ability and cell motility. Moreover, ET-1 induces activation of b1 integrin and downstream signaling. Mechanistically, ET1R/intb1 signaling allows ECM remodeling, either by promoting and invasive protrusion formation, invadosome, and collagen secretion. Importantly, therapeutical inhibition of ET-1 receptors with Ambrisentan and intβ1 with ATN-116 markedly reduced the ability of SOC cells to adhere in the intraperitoneal organs and to metastasize. Our findings support a model in which ET-1 educates the stromal fibroblasts to become permissive for tumor invasion and demonstrate for the time the significance of an ET-1-dependent integrin signaling in this process. Citation Format: Danila Del Rio, Valentina Caprara, Ilenia Masi, Francesca Spadaro, Sara Giannitelli, Alberto Rainer, Anna Bagnato, Laura Rosanò. Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6137.